Peptides have assumed considerable importance in pharmaceutical industry and vaccine research. Understanding the structural features of these peptide molecules can be effective not only in mimicking natural proteins but also in the design of new biomaterials. Polypeptide sequences consisting of twenty genetically coded amino acids possess structural flexibility, which makes the predictions difficult. However, the introduction of non-protein amino acids into the peptide chain restricts the available range of backbone conformations and acts as stereochemical directors of polypeptide chain folding. Such conformationally rigid residues allow the formation of well defined structures like helices, strands etc, which further assemble into super secondary structural motifs by flexible linkages. Crystal structure determination of the oligopeptides by X-ray diffraction gives insight into the specific conformational states, modes of aggregation, hydrogen bond interactions, solvation of peptides and various weakly polar interactions involving the side chains of aromatic residues (Phe, Trp and Tyr).

In ?-, ?- and higher ?-amino acids, due to the insertion of one or more methylene groups between the N- and C?-atoms into the peptide backbone the accessible conformational space is greater than the ?-amino acids. The ?-, ?-, ?-…. amino acid residues belong to the family of ?-amino acids. Extensive research in the field of ?-peptides, which have been experimentally verified or theoretically postulated, has assigned several helices, turns and sheets. The use of ?-amino acid residues in conjunction with ?-residues permits systematic exploration of the effects of introducing additional backbone atoms into well-characterized ?-peptide structures. The observation of new families of hydrogen bonded motifs in the hybrid peptides containing ?- and ?-amino acids are the recent interest in this regard.

Chapter 1 gives a general introduction to the stereochemistry of polypeptide chains and the secondary structure classification: helices, ?-sheets and ?-turns followed by an overview of different types of weakly polar interactions involving the side chains of aromatic amino acid residues. This section also provides a brief overview of the conformational analysis of ?-, ?- and higher ?-amino acid residues in oligomeric ?-peptides and in ?,?-hybrid peptides. A brief discussion on X-ray diffraction and solution to the phase problem is also presented.

Chapter 2 describes the crystal structures of the peptides, Boc-Leu-Trp-Val-OMe (LWV), the two polymorphs of Ac-Leu-Trp-Val-OMe (LWV1 and LWV2), Boc-Leu-Phe-Val-OMe (LFV), Ac-Leu-Phe-Val-OMe (LFV1) and Boc-Ala-Aib-Leu-Trp-Val-OMe (AULWV), in order to explore the nature of interactions between aromatic rings, specifically the indole side chain of Trp residues [1]. Peptide LWV adopts a type I ?-turn conformation, stabilized by an intramolecular 4?1 hydrogen bond. Molecules of LWV pack into helical columns stabilized by two intermolecular hydrogen bonds, Leu(1)NH…O=CTrp(2) and Indole NH…O=CLeu(1). The superhelical columns further pack into the tetragonal space group P43 by means of a continuous network of indole - indole interactions. The peptide Ac-Leu-Trp-Val-OMe crystallized in two polymorphic forms: P21 (LWV1) and P212121 (LWV2). In both forms, the peptide backbone is extended and the crystal packing shows anti-parallel ?-sheet arrangement. Similarly, extended strand conformation and anti-parallel ?-sheet formation are also observed in the Phe containing analogs, LFV and LFV1. The pentapeptide AULWV adopts a short stretch of 310-helix. Analysis of aromatic - aromatic and aromatic - amide interactions in the structures of peptides LWV, LWV1 and LWV2 are reported along with the examples of 12 Trp containing peptides from the Cambridge Structural Database. The results suggest that there is no dramatic preference for the orientation of two proximal indole rings. In Trp containing peptides specific orientations of the indole ring, with respect to the preceding and succeeding peptide units, appear to be preferred in ?-turns and extended structures.

Chapter 3 describes the crystal structures of three peptides containing Trp residues at both N- and C-termini of the peptide backbone: Boc-Trp-Trp-OMe (WW), Boc-Trp-Aib-Gly-Trp-OMe (WUGW) and Boc-Leu-Trp-Val-Ala-Aib-Leu-Trp-Val-OMe (H8AU). Peptide WW adopts an extended conformation and the molecules pack into an arrangement of parallel ?-sheet in crystals, stabilized by three intermolecular N-H…O hydrogen bonds. The potential hydrogen bonding group NE1H of Trp(1), which does not take part in hydrogen bonding interaction with an oxygen acceptor participate in an intermolecular N-H…? interaction. Peptide WUGW adopts a folded structure, stabilized by a consecutive type II-I’ ?-turn conformation. The crystal of WUGW contains a stoichiometric amount of chloroform in two distinct sites each with an occupancy factor of 0.5 and the structure provides examples of N-H…?, C-H…?, ?…?, N-H…Cl, C-H…Cl and C-H…O interactions [2]. The molecular conformation of H8AU reveals a 310-helix. The crystal structure of H8AU reveals an interesting packing motif in which helical columns are stabilized by side chain - backbone hydrogen bond involving the indole NH of Trp(2) as donor and C=O group of Leu(6) as acceptor of a neighboring molecule, which closely resembles the hydrogen bonding pattern obtained in the tripeptide LWV [1]. Helical columns also associate laterally and strong interactions are observed between the Trp(2) and Trp(7) residues on neighboring molecules [3]. The edge-to-face aromatic interactions between the indoles suggest a potential C-H…? interaction involving the CE3H of Trp (2)

Chapter 4 describes the crystal structures of four protected ?-amino acid residues, Boc-(S)-?3-HAla-NHMe (BANH); Boc-(R)-?3-HVal-NHMe (BVNH); Boc-(S)-?3-HPhe-NHMe (BFNH); Boc-(S)-?3-HPro-OH (BPOH) and two ?-dipeptides, Boc-(R)-?3-HVal-(R)-?3-HVal-OMe (BVBV); Boc-(R)-?3-HVal-(S)-?3-HVal-OMe (LVDV). Gauche conformations about the C?-C? bonds (? ~ ± 60°) are observed for the ?3-HPhe residue in BFNH and all four ?3-HVal residues in the dipeptides BVBV and LVDV. Trans conformations (? ~ 180°) are observed for ?3-HAla residues in both independent molecules in BANH and for the ?3-HVal and ?3-HPro residues in BVNH and BPOH, respectively. In all these cases except for BPOH, molecules associate in the crystals via intermolecular backbone hydrogen bonds leading to the formation of sheets. The polar strands formed by ?3-residues aggregate in both parallel (BANH, BFNH, LVDV) and anti-parallel (BVNH, BVBV) fashion. Sheet formation accommodates both the trans and gauche conformations about the C? - C? bonds [4].

Chapter 6 describes the crystal structures of five model peptides Piv-Pro-Gly-NHMe (PA1), Piv-Pro-?Gly-NHMe (PB1), Piv-Pro-?Gly-OMe (PBO), Piv-Pro-?Ava-OMe (PDAVA) and Boc-Pro-?Abu-OH (BGABU). A comparison of the structures of peptides PA1 and PB1 illustrates the dramatic consequences upon backbone homologation in short sequences. The molecule PA1 adopts a type II ?-turn conformation in the crystal state, while in PB1, the molecule adopts an open conformation with the ?-residue being fully extended. The peptide PBO, which differs from PB1 by replacement of the C-terminal NH group by an O-atom, adopts an almost identical molecular conformation and packing arrangement in the crystal state. In peptide PDAVA, the observed conformation resembles that determined for PB1 and PBO, with the ?Ava residue being fully extended. In peptide BGABU, the molecule undergoes a chain reversal, revealing a ?-turn mimetic structure stabilized by a C-H…O hydrogen bond [6].

Chapter 7 describes the crystal structures of a dipeptide, Boc-Aib-?Abu-OH (UG) and a tripeptide, Boc-Aib-?Abu-Aib-OMe (UGU) containing a single ?Abu residue in each sequence. The structure of UG forms a reverse turn stabilized by a 10-membered intramolecular C-H…O hydrogen bonded ring. The peptide UGU crystallized in the triclinic space group P?1 with two molecules in the asymmetric unit resulting in a parallel assembly of sheets in crystals. Notably, the insertion of a single Aib residue at the C-terminus drastically changes the overall conformation of the structures.